Meflocin has been first prepared (J. Med. Chem. 14 926 (1971)) by hydrating 2-pyridyl-2,8-bis(trifluoro-methyl)-quinolyl-ketone ("Ketone" hereinafter) above Adams catalyst and 2-pyridyl-2,8-bis(trifluor-methyl)-quinolyl-ketone is obtained from 2,8-bis(trifluoro-methyl)-quinoline-4-carboxylic acid synthetized in three steps with 2-lithio-pyridine. Starting from the above quinoline carboxylic acid intermediate "ketone" has been obtained also by reacting same with 2-bromo-magnesium-pyridine (DOS 29 40443) which analogously was hydrogenated to mefloquin in the presence of platina-charcoal catalyst. (2-pyridyl)-2,8-bis(trifluoro-methyl)-quinoline-4-methanol which is an unisolated intermediate of the reduction step is called hereinafter "Oxy-methane". This Oxy-methane can be also obtained by subjecting 2,8-bis(trifluoro-methyl)-4-bromo-quinoline to lithiation and by reacting the formed 4-lithio-quinoline derivative with 2-pyridine-aldehyde (DOS 28066909). According to a recent approach the metallation step is eliminated so that the use of less expensive starting material than quinoline intermediates became possible. By reacting 2,8-bis(trifluoro-methyl)-4-chloro-quinoline with 2-pyridyl-aceto-nitrile or 2-pyridyl-methyl-phosphoniumsalt "ketone" is obtained by oxidizing the formed intermediate. According to the authors for the nucleophilic substitution of the halogen of the quinoline in the four-position the pyridine derivative has to contain an electron withdrawing substituent on the methyl group (such as the above mentioned carbonitrile or phosphonium group) (EP 0049776).
The industrial realization of the above described processes has several disadvantages, such as the mentioned metallation steps and the expensive quinoline intermediates, such as 2,8-bis(trifluoro-methyl)-4-bromo-quinoline or the corresponding quinoline-4-carboxylic acid (due to the use of the expensive and not easily available pyridine derivatives as disclosed above.